Chest pain is a frequent symptom of patients with hypertrophic cardiomyopathy (HCM), commonly occurring in the setting of angiographically normal epicardial coronary arteries. In contrast to the generally reproducible effort angina of patients with coronary artery disease, HCM patients ofter report pain with variable threshold of onset, often prolonged in duration even after cessation of activity. Twenty patients with HCM and chest pain despite angiographically normal coronary arteries underwent a pacing study with measurement of great cardiac vein flow, lactate and oxygen content in addition to left ventricular filling pressure. A cohort of 28 patients without HCM who underwent the same pacing study without experiencing chest pain served as controls. During pacing coronary flow rose in both groups although coronary and myocardial hemodynamics differed greatly. In contrast to the linear increase in flow in control up to a heart rate of 150, HCM patients demonstrated an initial rise in flow at an intermediate heart rate, at which point 12 of 20 HCM patients described their typical chest pain. Continued pacing to a heart rate of 150 resulted in a fall in coronary flow in 14 of 20 HCM patients, associated with a substantial rise in left ventricular filling pressures and metabolic evidence of ischemia. A paradoxical narrowing of the arterial-venous oxygen difference was also noted, which may contribute to ischemia. Thus, most HCM patients achieve maximum coronary vasodilatation at modest increases in heart rate. Myocardial ischemia occurs at this point, resulting in elevation in left ventricular filling pressures, probably because of ischemia-related changes in ventricular compliance, with a subsequent adverse effect on coronary blood flow.